Therapeutic targeting of Glioblastoma Stem Cell survival and self-renewal signaling
Grant Award Details
Grant Type:
Grant Number:
DISC2-16774
Investigator(s):
Disease Focus:
Human Stem Cell Use:
Award Value:
$2,250,144
Status:
Active
Grant Application Details
Application Title:
Therapeutic targeting of Glioblastoma Stem Cell survival and self-renewal signaling
Public Abstract:
Research Objective
This DISC2 tests a strategy to target survival and self-renewal in glioma stem cells (GSC), and will identify a therapeutic candidate for safety, dosing and efficacy testing.
Impact
The glioma stem cell (GSC) population is resistant to radiation and DNA-targeted chemotherapy agents, driving tumor recurrence, and few therapeutic strategies have targeted GSC.
Major Proposed Activities
This DISC2 tests a strategy to target survival and self-renewal in glioma stem cells (GSC), and will identify a therapeutic candidate for safety, dosing and efficacy testing.
Impact
The glioma stem cell (GSC) population is resistant to radiation and DNA-targeted chemotherapy agents, driving tumor recurrence, and few therapeutic strategies have targeted GSC.
Major Proposed Activities
- Investigate C3a-C3aR signaling in additional primary glioblastoma (GBM) cell lines in vitro, testing effects on proliferation, survival, self-renewal and metabolism.
- Complete in silico design and screening of 100 RNAi candidates targeting C3aR expression with preliminary validation of sequences in HeLa cells, and 20 RNAi candidates for dose/cellular toxicity.
- Complete testing of two different conjugate chemistries for GBM cell transfection and therapeutic candidate distribution after in vivo delivery.
- Complete in vivo proof-of-concept testing for preliminary efficacy of 3 RNAi therapeutic candidates in combination with FLASH irradiation in an orthotopic GBM transplant model.
Statement of Benefit to California:
Glioblastoma (GBM) is the most common, aggressive, and lethal primary brain tumor. GBM has a median survival of 18-24 months. 70% of GBM patients exhibit progression/recurrence by 1 year after diagnosis and tumor resection, with less than 15% of patients surviving at 5 years. The glioma stem cell (GSC) population is associated with resistance to conventional therapy, contributing to tumor recurrence and emphasizing the need to target GSC to achieve effective treatment.
